Toxicity Reduction in the Treatment of HPV Positive Oropharyngeal Cancer: Emerging Combined Modality Approaches.
ABSTRACT: Human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) is a distinct clinical entity within the head and neck cancers, with a unique epidemiology and, in general, a favorable prognosis. Because of this favorable prognosis, researchers have considered de-intensifying the current standard treatment of HPV+ OPC in order to reduce acute and late treatment related toxicity without compromising outcome. Current ongoing trials can be divided in three main categories: de-intensification of the chemotherapy by replacing concomitant platinum-based chemotherapy with the EGFR-inhibitor cetuximab, or de-intensification of the radiation dose of either the primary radiotherapy of selected, good-responding patients after induction chemotherapy or of the adjuvant radiotherapy based on pathology features after primary surgery. Despite the good prognosis of the majority of HPV+ OPC patients, a proportion of them still have poor prognosis. This unmet need has led clinical research on new treatment strategies focused on influencing the unique micro-environment of HPV+ OPC with for example immunotherapy. This article summarizes the current understanding regarding the optimal treatment of non-metastatic HPV+ OPC. Ongoing and published clinical trials regarding de-intensification strategies, immunotherapy and proton therapy are described focusing on the rationale and underlying evidence of these emerging treatment strategies. Nevertheless, until the results of the ongoing trials are known, the treatment of HPV+ OPC in clinical practice should remain identical to the treatment of HPV negative OPC.
Project description:Current adjuvant treatment guidelines for oropharyngeal squamous cell carcinoma treated with primary surgery are based on studies that predate the human papillomavirus (HPV) era. HPV-associated oropharynx carcinoma (HPV-OPC) has a much more favorable prognosis compared to HPV-unassociated cancer and is increasingly considered to be a distinct disease entity due to its unique etiology, presentation, and behavior. Currently, there is significant interest in adjuvant treatment de-intensification of HPV-OPC patients in order to reduce treatment-related toxicity while maintaining excellent clinical outcomes. Here, we review the evidence and rationale underlying the ongoing prospective trials of adjuvant treatment de-intensification for HPV-OPC patients.
Project description:Background: With the growing interest in treatment de-intensification trials for human papillomavirus positive (HPV+) oropharyngeal squamous cell carcinoma (OPC), prognostic models have become essential for patient selection. The aim of this paper is to validate and compare the prognostic ability of the TNM 8th edition and previous published risk group classifications of Ang et al. and Rietbergen et al. and to derive a patient selection classification for de-intensification trials. Materials: Patients with HPV+ OPC treated with curative (chemo)radiotherapy between 2004 and 2017 were classified according to the TNM 8th edition, the model of Ang et al. and of Rietbergen et al. HPV status was determined by p16 immunohistochemistry staining. Overall survival was estimated using the Kaplan-Meier method and groups were compared using the log-rank test. Harrell's C-index was used as measure of discriminative performance. Results: A total of 333 OPC were identified of whom 100 were HPV+. The median follow-up was 63.7 months. The 5-year overall survival (5Y-OS) of stage I, II and III were 91.6, 55.2, and 38.0%. There was a significant difference between stage I vs. II and III. The Harrell's C-index for TNM 8th edition stage was 0.67. Including only HPV+ OPC, the Harrell's C-index for the model of Ang and Rietbergen were both 0.62. We combined the main prognostic factors defining the low risk groups in the three models, stage I, low comorbidity and ? 10 pack years, into one new low risk group to identify patients who may benefit from de-intensification trials. Intermediate risk was defined as stage I with high comorbidity or >10 pack years, high risk as stage II-III. The 5Y-OS were 100, 85.7, and 51.3%. The Harrell's C-index for the new classification model was 0.67. Conclusion: Although TNM 8th edition provides better OS stratification than the 7th edition, it is not performant enough for patient selection, neither are the models from Ang et al. and Rietbergen et al. Therefore, we propose a patient selection classification for de-intensification trials based on the new TNM classification 8th edition, comorbidity and smoking pack years. In addition, this study emphasizes the importance of patient selection and personalized treatment for HPV+OPC.
Project description:BACKGROUND:Patients with human papillomavirus-positive (HPV+) oropharyngeal squamous cell carcinoma (OPC) have substantially better treatment response and overall survival (OS) than patients with HPV-negative disease. Treatment options for HPV+ OPC can involve either a primary radiotherapy (RT) approach (± concomitant chemotherapy) or a primary surgical approach (± adjuvant radiation) with transoral surgery (TOS). These two treatment paradigms have different spectrums of toxicity. The goals of this study are to assess the OS of two de-escalation approaches (primary radiotherapy and primary TOS) compared to historical control, and to compare survival, toxicity and quality of life (QOL) profiles between the two approaches. METHODS:This is a multicenter phase II study randomizing one hundred and forty patients with T1-2?N0-2 HPV+ OPC in a 1:1 ratio between de-escalated primary radiotherapy (60?Gy)?±?concomitant chemotherapy and TOS?±?de-escalated adjuvant radiotherapy (50-60?Gy based on risk factors). Patients will be stratified based on smoking status (<?10 vs. ? 10 pack-years). The primary endpoint is OS of each arm compared to historical control; we hypothesize that a 2-year OS of 85% or greater will be achieved. Secondary endpoints include progression free survival, QOL and toxicity. DISCUSSION:This study will provide an assessment of two de-escalation approaches to the treatment of HPV+ OPC on oncologic outcomes, QOL and toxicity. Results will inform the design of future definitive phase III trials. TRIAL REGISTRATION:Clinicaltrials.gov identifier: NCT03210103. Date of registration: July 6, 2017, Current version: 1.3 on March 15, 2019.
Project description:Compare functional outcomes of radiotherapy (RT) concurrent with cetuximab (cet-RT) or with chemotherapy (chemo-RT) for comparable, good prognosis patients with human papillomavirus related (HPV+) oropharyngeal cancer (OPC).Outcomes of patients with stage III/IV HPV+ OPC patients with minimal smoking history and non-T4/N3/N2C, treated on prospective protocol of RT concurrent with cetuximab (cet-RT), were compared to similar patients on prospective chemo-RT protocols. In both groups, videofluoroscopy (VF), observer rated dysphagia (ORD), and validated QOL questionnaires: xerostomia questionnaire (XQ), head and neck QOL, and University of Washington QOL, were performed periodically and compared to pretreatment. Mixed effects models with adjustment for baseline assessed differences between groups.26 cet-RT patients were compared to 27 chemo-RT patients with similar baseline characteristics. In the chemo-RT group, no recurrences occurred. In the cet-RT group, 1 patient had persistent microscopic disease on salvage neck dissection and 1 distant failure. Both groups had mild VF-based swallowing dysfunction pre-treatment, worsened at 3 months (P<0.02) and persisted at 12 months, not differing between groups (P>0.11). For both groups ORD was very low pretreatment, worsened at 3 months and improved at 12 months, without differences between treatment groups (P=0.26). QOL Summary and domain scores for eating were good pretreatment, worse at 3 mo, and then improved to near baseline at 12 months, without differences between the groups in any QOL domains (P>0.10).Both groups had excellent clinical outcomes without significant differences in objective or subjective functions. These data question using cetuximab instead of chemotherapy for treatment de-intensification for HPV+ OPC.
Project description:Human papillomavirus-associated oropharynx cancer (HPVA-OPC) is rapidly increasing in incidence and has unique epidemiologic, molecular, and biologic characteristics. Despite being recognized as having superior prognosis, current evidence does not support less intense therapy compared with HPV-negative OPC. Current combined modality therapies confer a significant risk of morbidity, and patients with HPVA-OPC have a younger median age. These patients, therefore, live longer with the adverse effects of treatment, and this spurs the development of treatment deintensification trials that attempt to decrease treatment-related morbidity without compromising efficacy. Many radiation and chemotherapy de-escalation trials are underway. Minimally invasive surgical techniques are also being evaluated. It is important to identify the ideal patient group for treatment deintensification and to define prognostic risk groups to avoid undertreating the poorer-risk subset in HPVA-OPC, and validated biomarkers are needed to identify patients with the best prognosis. Significant smoking exposure mitigates the favorable prognosis of HPVA-OPC. Currently, less intense treatment is an option only in the setting of clinical trials, and patients with HPVA-OPC should be offered clinical trial options whenever they are available. Finally, recognition of novel therapeutic targets and signaling pathways is critical to the development of new treatment strategies that are desperately needed for patients with poor risk and those with recurrent and metastatic disease.
Project description:<h4>Background</h4>Current standard radiotherapy for oropharynx cancer (OPC) is associated with high rates of severe toxicities, shown to adversely impact patients' quality of life. Given excellent outcomes of human papilloma virus (HPV)-associated OPC and long-term survival of these typically young patients, treatment de-intensification aimed at improving survivorship while maintaining excellent disease control is now a central concern. The recent implementation of magnetic resonance image - guided radiotherapy (MRgRT) systems allows for individual tumor response assessment during treatment and offers possibility of personalized dose-reduction. In this 2-stage Bayesian phase II study, we propose to examine weekly radiotherapy dose-adaptation based on magnetic resonance imaging (MRI) evaluated tumor response. Individual patient's plan will be designed to optimize dose reduction to organs at risk and minimize locoregional failure probability based on serial MRI during RT. Our primary aim is to assess the non-inferiority of MRgRT dose adaptation for patients with low risk HPV-associated OPC compared to historical control, as measured by Bayesian posterior probability of locoregional control (LRC).<h4>Methods</h4>Patients with T1-2?N0-2b (as per AJCC 7th Edition) HPV-positive OPC, with lymph node <3?cm and <10 pack-year smoking history planned for curative radiotherapy alone to a dose of 70?Gy in 33 fractions will be eligible. All patients will undergo pre-treatment MRI and at least weekly intra-treatment MRI. Patients undergoing MRgRT will have weekly adaptation of high dose planning target volume based on gross tumor volume response. The stage 1 of this study will enroll 15 patients to MRgRT dose adaptation. If LRC at 6?months with MRgRT dose adaptation is found sufficiently safe as per the Bayesian model, stage 2 of the protocol will expand enrollment to an additional 60 patients, randomized to either MRgRT or standard IMRT.<h4>Discussion</h4>Multiple methods for safe treatment de-escalation in patients with HPV-positive OPC are currently being studied. By leveraging the ability of advanced MRI techniques to visualize tumor and soft tissues through the course of treatment, this protocol proposes a workflow for safe personalized radiation dose-reduction in good responders with radiosensitive tumors, while ensuring tumoricidal dose to more radioresistant tumors. MRgRT dose adaptation could translate in reduced long term radiation toxicities and improved survivorship while maintaining excellent LRC outcomes in favorable OPC.<h4>Trial registration</h4>ClinicalTrials.gov ID: NCT03224000; Registration date: 07/21/2017.
Project description:The prognosis of HPV-positive squamous oropharyngeal carcinomas (OPCs) is more favorable than that of HPV-negative OPCs. However, the prognosis of some of these tumors is dismal and to date validated survival predictors are missing in clinical practice. We designed a study on HPV-positive OPCs to determine whether a previously published gene expression tumor classification model,defined through meta-analysis of publicly available datasets (PMCID: PMC6721309), is able to predict survival in an external patient cohort. The 3 gene expression clusters were tested in a validation set of 286 cases and in a refined study population of 235 patients and in both confirmed their prognostic value. Five-year OS was 95% in the low risk cluster Cl1, 80% in the intermediate risk cluster (HR=5.74, p=.0057), and 66% in the high risk cluster (HR=9.28, p=.001). Functional/biological cluster characterization identified potentially targetable pathways in the high risk cluster. This prognostic stratification might be useful for clinical decision making and for planning future trials based on molecular tumor features. Overall design: In our work, we considered a cohort of the HPV positive OPC patients included in the project “Big Data and Models for Personalized Head and Neck Cancer Decision Support (BD2Decide)”, trial registry ClinicalTrial.gov number NCT02832102. Patients were treated in seven European referral cancer centers (Italy, The Netherlands and Germany) with expertise in the multidisciplinary management of head and neck cancer patients. Median follow-up was 46.2 months (95% confidence interval 41.2-50) and data collection was concluded in September 2019 (doi:10.1002/hed.26515). OPC patients with loco-regionally advanced non-metastatic disease treated with curative intent were tested for HPV using p16-immunostaining and HPV DNA PCR and when positive included. HPV status was assessed by p16-immunostaining followed by a HPV DNA PCR test on the p16-immunopositive cases. Patients were treated with multimodal strategies (combinations of surgery, radiotherapy, and chemotherapy). For T1N1M0 and T2N1M0 disease single-modality treatment (surgery or radiotherapy) was allowed. To reduce the bias of confounding variables impacting on outcome, we excluded OPC: i) patients with p16-positive but HPV-DNA-negative OPC; ii) patients receiving unimodal treatment (surgery without post-operative radiation or exclusive radiotherapy without concomitant systemic treatments) for clinical stage T1N>1, T2N>1 and T3-T4 any N disease. TNM7= AJCC/UICC staging system 7th edition; TNM8= AJCC/UICC staging system 8th edition; subset (n=235)= exclusion of 51 HPV-DNA negative (n=14) OPCs and suboptimal treatments (n=37); HPV_molecular_clusters= gene-expression stratification based on Locati et al (PMCID: PMC6721309).
Project description:Oropharyngeal cancers caused by human papillomaviruses (HPV) have a different epidemiology, prognosis, genetic mutational landscape, response to treatment, and outcome when compared to HPV-negative cancers. In this review, a summary of our current understanding of HPV in head and neck cancer and the important advances that have shown HPV to be an etiological agent are discussed. HPV-positive and HPV-negative tumors are compared discussing clinicopathological factors, prognosis, outcome following treatment, and the molecular and genetic differences. Currently, the standard of care for oropharyngeal cancer is both surgery and post-operative radiotherapy with or without cisplatin or concurrent chemo-radiotherapy. The latter is used more often, especially in cancers of tonsil and base of tongue. However, there is increased interest in trying to de-intensify treatment and in the development of new treatments to target the underlying different molecular pathways of HPV-positive cancers. The current clinical trials involving surgery, chemotherapy, and radiation therapy are discussed. The new targeted treatments are also summarized. Although there is currently is no evidence from prospective studies to support a change in the treatment algorithm, the treatment options for patients with HPV-positive disease are likely to change in the future.
Project description:Background: Anti-epidermal-growth-factor-receptor (EGFR) therapies in combination with radiotherapy are being studied on de-escalation clinical trials for HPV-related oropharyngeal cancer (OPC) patients. The HPV16-E5 oncoprotein increases recycling of activated EGFR to the cell surface, enhancing factor signal transduction. Our aim was to evaluate viral HPV16-E5 oncogene expression as well as EGFR and phosphorylated-EGFR (pEGFR), protein levels as biomarkers for clinical outcome in a retrospective cohort of OPC patients. Methods: Formalin-fixed-paraffin-embedded OPCs were collected from 1990 to 2013. OPC samples containing HPV-DNA were subject to viral E6 * I mRNA detection and p16INK4a immunohistochemistry (IHC). HPV16-positive cases were evaluated for HPV16-E5 (RT-PCR) and EGFR/pEGFR (IHC). A stratified and matched random sample of HPV-negative samples was used as control and evaluated for EGFR/pEGFR. Overall survival (OS) and disease free survival (DFS) estimates were assessed for locally advanced OPC patients (stage III, IVa,b 7th edition). Results: Among 788 OPC patient samples, 53 were double positive for HPV16-DNA/p16INK4a. HPV16-E5 expression was found in 41 of 53 samples (77.4%). EGFR expression was observed in 37.7 vs 70.8% of HPV16-positive vs HPV-negative samples, respectively; (adjusted OR = 0.15) 5% CI = 0.04-0.56]). Expression of pEGFR followed an inverse pattern with 39.6 and 24.9% detection in HPV16-positive and HPV-negative samples; (adjusted OR = 1.58 [95% CI = 0.48-5.17]). Within HPV16-positive cases, no association between HPV16-E5/EGFR nor pEGFR was observed. With a median follow-up of 39.36 months (min = 0.03 - max = 272.07), the combination of HPV status and EGFR or pEGFR expression were predictors of better OS (p < 0.001, for both) and DFS (p < 0.001 for EGFR and p = 0.003 for pEGFR). Conclusions: HPV16-E5 is highly expressed on HPV16-positive OPCs. Interestingly, HPV16-positive cases expressed significantly more pEGFR while HPV-negative cases expressed more EGFR. The combinations of HPV status and EGFR or pEGFR may be useful biomarkers for evaluating prognosis outcome in OPC patients.
Project description:PATHOS is a phase II/III randomized controlled trial (RCT) of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery (TOS) for human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC). The study opened in the UK in October 2015 and, after successful recruitment into the phase II, transitioned into phase III in the autumn of 2018. PATHOS aims to establish whether the de-intensification of adjuvant treatment in patients with favorable prognosis HPV-positive OPSCC will confer improved swallowing outcomes, whilst maintaining high rates of cure. In this article, we will outline the rationale for the study and how it aims to answer fundamentally important questions about the safety, effectiveness and functional outcomes of minimally invasive TOS techniques followed by adjuvant radiotherapy (RT) or chemo-radiotherapy (CRT) in this patient population.